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WO2001081315A2 - Amino-imidazole derivatives for treating cancer - Google Patents

Amino-imidazole derivatives for treating cancer Download PDF

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Publication number
WO2001081315A2
WO2001081315A2 PCT/US2001/013060 US0113060W WO0181315A2 WO 2001081315 A2 WO2001081315 A2 WO 2001081315A2 US 0113060 W US0113060 W US 0113060W WO 0181315 A2 WO0181315 A2 WO 0181315A2
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cancer
imidazole
carcinoma
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WO2001081315A3 (en
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James Berger Camden
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Procter and Gamble Co
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Procter and Gamble Co
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/88—Nitrogen atoms, e.g. allantoin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • TECHNICAL FIELD A method of treating cancer, including carcinomas and sarcomas is claimed.
  • the pharmaceutical composition containing imidazole-l,2-diamine compounds is also claimed. BACKGROUND OF THE INVENTION
  • Cancers are a leading cause of death in animals and humans.
  • the exact cause of cancer is not known, but links between certain activities such as smoking or exposure to carcinogens and the incidence of certain types of cancers and tumors has been shown by a number of researchers.
  • Many types of chemotherapeutic agents have been shown to be effective against cancers and tumor cells, but not all types of cancers and tumors respond to these agents. Unfortunately, many of these agents also destroy normal. cells. The exact mechanism for the action of these chemotherapeutic agents is not always known.
  • cytocidal or cytostatic agents work best on cancers with large growth factors, i.e., ones whose cells are rapidly dividing.
  • hormones in particular estrogen, progesterone and testosterone, and some antibiotics produced by a variety of microbes, alkylating agents, and anti -metabolites form the bulk of therapies available to oncologists.
  • cytotoxic agents that have specificity for cancer and tumor cells while not affecting normal cells would be extremely desirable. Unfortunately, none have been found and instead agents which target especially rapidly dividing cells (both tumor and normal) have been used.
  • a method of treating cancer comprising administering a therapeutically effective amount of a composition comprising one or more imidazole-l,2-diamine compounds having the formula:
  • Y and X are independently selected from the group consisting of hydrogen, halogen, e.g., chloro or fluoro, nitro, methyl, ethyl, oxychloro or alkoxy of less than 7 carbon atoms; n is a positive integer of less than 5; Ri and R 2 is independently selected from the group consisting of hydrogen and alkyl of less than 7 carbons, and R is an alkyl of from 1 to 6 carbons.
  • the compound has the formula:
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound as described above.
  • compositions have been discovered to inhibit the growth of cancer or other tumors in humans or animals by administration of a therapeutically effective amount of the composition, preferably by administering one or more imidazole-l,2-diamine compounds to the site of the cancer. More specifically, this invention provides an anti-cancer composition comprising a pharmaceutical carrier and imidazole-l,2-diamine derivative as defined herein along with a method for treating such cancers.
  • a "pharmaceutically acceptable” component is one that is suitable for use with humans and/or animals without undue adverse side effects (such as toxicity, irritation, and allergic response) commensurate with a reasonable benefit/risk ratio.
  • safe and effective amount refers to the quantity of a component which is sufficient to yield a desired therapeutic response without undue adverse side effects (such as toxicity, irritation, or allergic response) commensurate with a reasonable benefit/risk ratio when used in the manner of this invention.
  • terapéuticaally effective amount is meant an amount of a compound of the present invention effective to yield the desired therapeutic response. For example, an amount effective to delay the growth of or to cause a cancer, either a sarcoma or lymphoma, to shrink or not metastasize.
  • the specific safe and effective amount or therapeutically effective amount will vary with such factors as the particular condition being treated, the physical condition of the patient, the type of mammal being treated, the duration of the treatment, the nature of concurrent therapy (if any), and the specific formulations employed and the structure of the compound or its derivative.
  • a "pharmaceutical salt” is salt of the imidazole-l,2-diamine derivatives which has been modified by making acid or base salts of the compounds.
  • pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines.
  • the salts are made using an organic or inorganic acid.
  • These preferred acid salts are chlorides, bromides, sulfates, nitrates, phosphates, sulfonates, formates, tartrates, maleates, malates, citrates, benzoates, salicylates, ascorbates, and the like.
  • a “pharmaceutical carrier” is a pharmaceutically acceptable solvent, suspending agent or vehicle, for delivering the imidazole-l,2-diamine to the animal or human.
  • the carrier may be liquid or solid and is selected with the planned manner of administration in mind.
  • Liposomes are also a pharmaceutical carrier.
  • cancer refers to all types of cancer or neoplasm or malignant tumors found in mammals, including carcinomas and sarcomas. Examples of cancers are cancer of the breast, colon, lung, non-small cell lung, melanoma, ovary, prostate and pancreas.
  • leukemia refers broadly to progressive, malignant diseases of the blood-forming organs and is generally characterized by a distorted proliferation and development of leukocytes and their precursors in the blood and bone marrow. Leukemia is generally clinically classified on the basis of (1) the duration and character of the disease- acute or chronic; (2) the type of cell involved; myeloid (myelogenous), lymphoid (lymphogenous), or monocytic; and (3) the increase or non-increase in the number abnormal cells in the blood- leukemic or aleukemic (subleukemic).
  • the P388 leukemia model is widely accepted as being predictive of in vivo anti-leukemic activity.
  • the present invention includes a method of treating leukemia, and, preferably, a method of treating acute nonlymphocytic leukemia, chronic lymphocytic leukemia, acute granulocytic leukemia, chronic granulocytic leukemia, acute promyelocytic leukemia, adult T-cell leukemia, aleukemic leukemia, a leukocythemic leukemia, basophylic leukemia, blast cell leukemia, bovine leukemia, chronic myelocytic leukemia, leukemia cutis, embryonal leukemia, eosinophilic leukemia, Gross' leukemia, hairy-cell leukemia, hemoblastic leukemia, hemocytoblastic leukemia, histiocytic leukemia, stem cell leukemia, acute monoc
  • melanoma generally refers to a tumor arising from the melanocytic system of the skin and other organs.
  • Melanomas which can be treated with imidazole- 1,2-diamine and optionally a potentiator and/or another chemotherapeutic agent include, for example, acral-lentiginous melanoma, amelanotic melanoma, benign juvenile melanoma, Cloudman's melanoma, S91 melanoma, Harding-Passey melanoma, juvenile melanoma, lentigo maligna melanoma, malignant melanoma, nodular melanoma, subungal melanoma, and superficial spreading melanoma.
  • carcinoma refers to a malignant new growth made up of epithelial cells tending to infiltrate the surrounding tissues and give rise to metastases.
  • exemplary carcinomas which can be treated with imidazole-l,2-diamine and optionally a potentiator and/or a chemotherapeutic agent include, for example, acinar carcinoma, acinous carcinoma, adenocystic carcinoma, adenoid cystic carcinoma, carcinoma adenomatosum, carcinoma of adrenal cortex, alveolar carcinoma, alveolar cell carcinoma, basal cell carcinoma, carcinoma basocellulare, basaloid carcinoma, basosquamous cell carcinoma, bronchioalveolar carcinoma, bronchiolar carcinoma, bronchogenic carcinoma, cerebriform carcinoma, cholangiocellular carcinoma, chorionic carcinoma, colloid carcinoma, comedo carcinoma, corpus carcinoma, cribriform carcinoma, carcinoma en cuirasse, carcinoma cutaneum, cylindrical carcinoma, cylindrical cell carcinoma, duct carcinoma, carcinoma durum, embryonal carcinoma,
  • Additional cancers which can be treated with imidazole-l,2-diamine according to the invention include, for example, Hodgkin's Disease, Non-Hodgkin's Lymphoma, multiple myeloma, neuroblastoma, breast cancer, ovarian cancer, lung cancer, rhabdomyosarcoma, primary thrombocytosis, primary macroglobulinemia, small-cell lung tumors, primary brain tumors, stomach cancer, colon cancer, malignant pancreatic insulanoma, malignant carcinoid, urinary bladder cancer, premalignant skin lesions, testicular cancer, lymphomas, thyroid cancer, esophageal cancer, genitourinary tract cancer, malignant hypercalcemia, cervical cancer, endometrial cancer, adrenal cortical cancer, and prostate cancer.
  • the "imidazole-l,2-diamine” or “imidazole-l,2-diamine derivatives” or "imidazole-l,2-diamine compounds” are the compounds
  • Y and X are independently selected from the group consisting of hydrogen, halogen, e.g., chloro, fluoro, nitro, methyl, ethyl, oxychloro or alkoxy of less than 7 carbon atoms; n is a positive integer of less than 5; Ri and R 2 are independently selected from the group consisting of hydrogen and alkyl of less than 7 carbons; and R is an alkyl of from 1 to 6 carbons; and its pharmaceutically safe salts and prodrugs thereof. More specific imidazole-l,2-diamines are described in detail below.
  • alkyl as used herein is meant a straight, branched or cyclic alkane derivatives.
  • combination therapy or "adjunct therapy” means that the patient in need of the drug is treated or given another drug for the disease in conjunction with the imidazole-l,2-diamine derivatives.
  • This combination therapy can be sequential therapy where the patient is treated first with one drug and then the other or the two drugs are given simultaneously.
  • Y and X are independently selected form the group consisting of hydrogen, halogen, e.g., chloro, fluoro, nitro, methyl, ethyl, oxychloro or alkoxy of less than 7 carbon atoms; n is a positive integer of less than 5; and R 2 are independently selected from the group consisting of hydrogen and alkyl of less than 7 carbons; and R is alkyl of 1 to 6 carbons.
  • the compositions are:
  • R is methyl, Rj and R 2 are hydrogen and X and Y are hydrogen and n is 4; and the non-toxic, pharmaceutically acceptable acid salts with both organic and inorganic acids.
  • the imidazole-l,2-diamine compounds also include prodrugs.
  • “Prodrugs” are considered to be any covalently bonded carriers which release the active parent drug according to the formula of the imidazole-l,2-diamine derivatives described above in vivo when such prodrug is administered to a mammalian subject.
  • Prodrugs of the imidazole-l,2-diamine compounds are prepared by modifying functional groups present in the compounds in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compounds.
  • Prodrugs include compounds wherein hydroxy, amine, or sulfhydryl groups are bonded to any group that, when administered to a mammalian subject, cleaves to form a free hydroxyl, amino, or sulfhydryl group, respectively.
  • Examples of prodrugs include, but are not limited to, acetate, formate, or benzoate derivatives of alcohol and amine functional groups in the imidazole-1,2- diamine; phosphate esters, dimethylglycine esters, aminoalkylbenzyl esters, aminoalkyl esters and carboxyalkyl esters of alcohol or phenol functional groups in the imidazole- 1,2-diamine; and the like.
  • the pharmaceutically acceptable salts of the imidazole-l,2-diamine include the conventional non-toxic salts or the quaternary ammonium salts of the imidazole-1,2- diamine formed, for example, from non-toxic inorganic or organic acids.
  • such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, formic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like.
  • inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like
  • organic acids such as acetic, propionic, succinic, glycolic, stearic,
  • a pharmaceutically acceptable salt of the present invention is synthesized from the imidazole-l,2-diamine derivatives which contain a basic moiety by conventional chemical methods.
  • such salts are prepared by reacting the free base forms of these compounds with a stoichiometric amount of the appropriate acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418. SYNTHESIS
  • imidazole-l,2-diaminederivatives are prepared in a number of ways well known to one skilled in the art of organic synthesis.
  • 2-amino-l-(4-methoxybenzyliden)amino-4-phenylimidazole is prepared by reacting N-amidino-N' - (4-methoxybenizylidene)hydrazone and 2-bromoacetophenone (see, M.Z. Krimer, et al., Chemistry ofHeterocyclic Compounds, 9, 1209-1213 (Russian) 1999; (English, pp. 1035-1039).
  • N-amidino-N' - (4-methoxybenizylidene)hydrazone is made by reacting p-anisaldehyde and aminoguanidinium nitrate in the presence of potassium hydroxide in ethanol (A. F. Hegarty, et al, J Chem. Soc, Perkin II, 1973, 2047-2054). The synthesis is described in Example 2.
  • imidazole-l,2-diamine is used in combination with one or more potentiators and/or chemotherapeutic agents for the treatment of cancer or tumors.
  • An exemplary potentiator is triprolidine or its cis-isomer which are used in combination with chemotherapeutic agents and imidazole-l,2-diamine.
  • Triprolidine is described in US 5,114,951 (1992).
  • Another potentiator is procodazole, lH-Benzimidazole-2- propanoic acid; [ ⁇ -(2-benzimidazole) propionic acid; 2-(2-carboxyethyl)benzimidazole; propazol].
  • Procodazole is a non-specific immunoprotective agent active against viral and bacterial. It is effective with imidazole-l,2-diamine in treating cancers, tumors or leukemia. Procodazole can also be combined with imidazole-l,2-diamine and other chemotherapeutic agents to treat cancer, tumor or leukemia.
  • the chemotherapeutic agents which can be used with imidazole-l,2-diamine and an optional potentiator are generally grouped as DNA-interactive Agents, Antimetabolites, Tubulin-Interactive Agents, Hormonal agents and others such as Asparaginase or hydroxyurea. Each of the groups of chemotherapeutic agents can be further divided by type of activity or compound.
  • the chemotherapeutic agents used in combination with imidazole-l,2-diamine include members of all of these groups.
  • DNA-Interactive Agents include the alkylating agents, e.g. Cisplatin,
  • Cyclophosphamide Altretamine
  • the DNA strand-breakage agents such as Bleomycin
  • the intercalating topoisomerase II inhibitors e.g., Dactinomycin and Doxorubicin
  • the nonintercalating topoisomerase II inhibitors such as, Etoposide and Teniposde
  • the alkylating agents form covalent chemical adducts with cellular DNA, RNA, and protein molecules and with smaller amino acids, glutathione and similar chemicals. Generally, these alkylating agents react with a nucleophilic atom in a cellular constituent, such as an amino, carboxyl, phosphate, sulfhydryl group in nucleic acids, proteins, amino acids, or glutathione. The mechanism and the role of these alkylating agents in cancer therapy is not well understood.
  • Typical alkylating agents include:
  • Nitrogen mustards such as Chlorambucil, Cyclophosphamide, Isofamide, Mechlorethamine, Melphalan, Uracil mustard; Aziridine such as Thiotepa; methanesulphonate esters such as Busulfan; nitroso ureas, such as Carmustine, Lomustine, Streptozocin; platinum complexes, such as Cisplatin, Carboplatin; bioreductive alkylator, such as Mitomycin, and Procarbazine, dacarbazine and
  • DNA strand breaking agents include Bleomycin.
  • DNA topoisomerase II inhibitors include the following:
  • Intercalators such as Amsacrine, Dactinomycin, Daunorubicin, Doxorubicin, Idarubicin, and Mitoxantrone; and nonintercalators, such as Etoposide and Teniposide.
  • the DNA minor groove binder is Plicamycin.
  • the antimetabolites interfere with the production of nucleic acids by one or the other of two major mechanisms. Some of the drugs inhibit production of the deoxyribonucleoside triphosphates that are the immediate precursors for DNA synthesis, thus inhibiting DNA replication. Some of the compounds are sufficiently like purines or pyrimidines to be able to substitute for them in the anabolic nucleotide pathways. These analogs can then be substituted into the DNA and RNA instead of their normal counterparts.
  • the antimetabolites useful herein include: folate antagonists such as Methotrexate and trimetrexate pyrimidine antagonists, such as Fluorouracil, Fluorodeoxyuridine, CB3717,
  • Tubulin Interactive agents act by binding to specific sites on tubulin, a protein that polymerizes to form cellular microtubules. Microtubules are critical cell structure units. When the interactive agents bind on the protein, the cell can not form microtubules
  • Tubulin Interactive agents include colchicine, Vincristine and Vinblastine, both alkaloids and Paclitaxel and cytoxan. Hormonal agents are also useful in the treatment of cancers and tumors.
  • estrogens are used in hormonally susceptible tumors and are usually derived from natural sources. These include: estrogens, conjugated estrogens and Ethinyl Estradiol and Diethylstilbesterol, Chlortrianisen and Idenestrol; progestins such as Hydroxyprogesterone caproate, Medroxyprogesterone, and
  • Megestrol androgens such as testosterone, testosterone propionate; fluoxymesterone, methyltestosterone.
  • Adrenal corticosteroids are derived from natural adrenal cortisol or hydrocortisone. They are used because of their anti inflammatory benefits as well as the ability of some to inhibit mitotic divisions and to halt DNA synthesis. These compounds include, Prednisone, Dexamethasone, Meth lprednisolone, and Prednisolone.
  • Leutinizing hormone releasing hormone agents or gonadotropin-releasing hormone antagonists are used primarily the treatment of prostate cancer. These include leuprolide acetate and goserelin acetate. They prevent the biosynthesis of steroids in the testes.
  • Antihormonal antigens include: antiestrogenic agents such as Tamoxifen, antiandrogen agents such as Flutamide; and antiadrenal agents such as Mitotane and Aminoglutethimide. Hydroxyurea, which appears to act primarily through inhibition of the enzyme ribonucleotide reductase, can also be used in combination with imidazole-l,2-diamine.
  • Asparaginase is an enzyme which converts asparagine to nonfunctional aspartic acid and thus blocks protein synthesis in the tumor. Asparaginase can also be used in combination with imidazole-l,2-diamine to treat cancer. DOSAGE
  • Imidazole-l,2-diamine is preferably micronized or powdered so that it is more easily dispersed and solubilized by the body.
  • Processes for grinding or pulverizing drugs are well known in the art. For example, a hammer mill or similar milling device are used.
  • the preferred particle size is less than about lOO ⁇ and preferably less than 50 ⁇ .
  • Dosage forms (compositions) suitable for internal administration contain from about 1.0 milligram to about 5000 milligrams of active ingredient per unit. In these pharmaceutical compositions, the active ingredient will ordinarily be present in an amount of about 0.5-95% by weight based on the total weight of the composition.
  • the dosage may be administered in one or more doses several times per day or per week. Multiple dosage units may be required to achieve a therapeutically effective amount. For example, if the dosage form is 1000 mg, and the patient weighs 40 kg, one pill will provide a dose of 25 mg per kg for that patient. It will provide a dose of only 12.5 mg/kg for a 80 kg patient.
  • Imidazole-l,2-diamine has exhibited efficacy in vivo against cancers in mice at doses of about 500 mg/kg, 750 mg/kg and 1000 mg/kg.
  • an effective dose in mice is about 12 times the expected effective dose in humans.
  • a dosage of as little as about 25 milligrams (mg) per kilogram (kg) of body weight and up to about 10000 mg per kg of body weight is suitable as a therapeutically effective dose.
  • Preferably, from about 40 mg/kg to about 2500 mg/kg of body weight is used.
  • Other preferred doses range between 100 mg/kg to about 3000 mg/kg of body weight.
  • a dosage of between about 2 milligrams (mg) per kilogram (kg) of body weight to about 400 mg per kg of body weight is also suitable for treating some cancers.
  • Imidazole-l,2-diamine may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three, or four times daily. Imidazole-l,2-diamine is generally given in one or more doses on a daily basis or from one to three times a week.
  • Imidazole-l,2-diamine is administered by any conventional means available for use in conjunction with pharmaceuticals, either as individual therapeutic agents or in combination with other therapeutic agents
  • a chemotherapeutic agent that is used with imidazole- 1,2-diamine in treating cancer, tumor, leukemia, or other related diseases will vary according to patient response and physiology, type and severity of side effects, disease being treated, dosing regimen, patient prognosis or other such factors.
  • the ratio of imidazole-l,2-diamine to the other therapeutic agent will be varied as needed according to the desired therapeutic effect, the observed side-effects of the combination, or other such considerations known to those of ordinary skill in the medical arts.
  • the ratio of imidazole-l,2-diamine to other therapeutic agent will range from about 0.5% : 99.5% to about 99.5% : 0.5% on a weight basis.
  • the respective doses and the dosing regimen of imidazole-l,2-diamine and the other therapeutic agent may vary.
  • the adjunct or combination therapy can be sequential, that is the treatment with one agent first and then the second agent, or it can be concomitant treatment wherein two or more agents are administered substantially at the same time.
  • the sequential therapy can be within a reasonable time after the completion of the first therapy before beginning the second therapy.
  • the treatment with both agents at the same time can be in the same daily dose or in separate doses. For example treatment with one agent on day 1 and the other on day 2. The exact regimen will depend on the disease being treated, the severity of the disease and the response to the treatment.
  • a full dosing regimen of imidazole- 1,2-diamine can be administered either before or after a full dosing regimen of the other therapeutic agent, or alternating doses of imidazole- 1,2-diamine and the other therapeutic agent may be administered.
  • imidazole- 1,2-diamine can be administered concomitantly with the other therapeutic agent.
  • the identity of the chemotherapeutic agent, the pharmaceutical carrier and the amount of compound administered will vary widely depending on the species and body weight of mammal and the type of cancer being treated.
  • the dosage administered will vary depending upon known factors, such as the pharmacodynamic characteristics of a specific chemotherapeutic agent and its mode and route of administration; the age, sex, metabolic rate, absorptive efficiency, health and weight of the recipient; the nature and extent of the symptoms; the kind of concurrent treatment being administered; the frequency of treatment; and the desired therapeutic effect.
  • Imidazole- 1,2-diamine, the potentiator and/or the chemotherapeutic agent are administered together in a single dosage form or separately in two or more different dosage forms. These can be administered independently by the same route or by two or more different routes of administration depending on the dosage forms employed.
  • Suitable pharmaceutical compositions and dosage forms will preferably comprise imidazole- 1,2-diamine, a potentiator and optionally a chemotherapeutic agent.
  • the ratio of imidazole- 1,2-diamine to potentiator is generally in the range of about 1:0.01 to 10:1, and preferably 1:0.05 to 1:1 on a weight basis.
  • a dosage unit may comprise a single compound or mixtures thereof with other anti-cancer compounds, other cancer or tumor growth inhibiting compounds.
  • Imidazole- 1,2-diamine can be administered in oral dosage forms as tablets, capsules, pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions.
  • Imidazole- 1,2-diamine may also be administered in intravenous (bolus or infusion), intraperitoneal, subcutaneous, or intramuscular form, all using dosage forms well known to those of ordinary skill in the pharmaceutical arts.
  • Imidazole- 1,2-diamine is typically administered in admixture with suitable pharmaceutical diluents, extenders, excipients, or carriers (collectively referred to herein as a pharmaceutically acceptable carrier or carrier materials) suitably selected with respect to the intended form of administration and as consistent with conventional pharmaceutical practices.
  • suitable pharmaceutical diluents, extenders, excipients, or carriers (collectively referred to herein as a pharmaceutically acceptable carrier or carrier materials) suitably selected with respect to the intended form of administration and as consistent with conventional pharmaceutical practices.
  • the unit will be in a form suitable for oral, rectal, topical, intravenous injection or parenteral administration.
  • Imidazole- 1,2-diamine can be administered alone but is generally mixed with a pharmaceutically acceptable carrier.
  • This carrier can be a solid or liquid, and the type of carrier is generally chosen based on the type of administration being used.
  • Specific examples of pharmaceutical acceptable carriers and excipients that may be used to formulate oral dosage forms of the present invention are described in U. S. Pat. No. 3,903,297 to Robert, issued Sept. 2, 1975.
  • Tablets may contain suitable binders, lubricants, disintegrating agents, coloring agents, flavoring agents, flow-inducing agents, and melting agents.
  • the active drug component can be combined with an oral, non-toxic, pharmaceutically acceptable, inert carrier such as lactose, gelatin, agar, starch, sucrose, glucose, methyl cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like.
  • Suitable binders include starch, gelatin, natural sugars such as glucose or beta- lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth, or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and the like.
  • Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like.
  • Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum, and the like.
  • Imidazole- 1,2-diamine may also be coupled to soluble polymers as targetable drug carriers or as a prodrug.
  • soluble polymers include polyvinylpyrrolidone, pyran copolymer, polyhydroxylpropylmethacrylamide-phenol, polyhydroxyethylasparta-midephenol, or polyethyleneoxide-polylysine substituted with palmitoyl residues.
  • imidazole- 1,2-diamine may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacylates, and crosslinked or amphipathic block copolymers of hydrogels.
  • Gelatin capsules may contain the active ingredient and powdered carriers, such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like. Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as immediate release products or as sustained release products to provide for continuous release of medication over a period of hours. Compressed tablets can be sugar coated or film coated to mask any unpleasant taste and protect the tablet from the atmosphere, or enteric coated for selective disintegration in the gastrointestinal tract.
  • the oral drug components are combined with any oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like.
  • suitable liquid dosage forms include solutions or suspensions in water, pharmaceutically acceptable fats and oils, alcohols or other organic solvents, including esters, emulsions, syrups or elixirs, suspensions, solutions and/or suspensions reconstituted from non-effervescent granules and effervescent preparations reconstituted from effervescent granules.
  • Such liquid dosage forms may contain, for example, suitable solvents, preservatives, emulsifying agents, suspending agents, diluents, sweeteners, thickeners, and melting agents.
  • Liquid dosage forms for oral administration can contain coloring and flavoring to increase patient acceptance.
  • water a suitable oil, saline, aqueous dextrose (glucose), and related sugar solutions and glycols such as propylene glycol or polyethylene glycols are suitable carriers for parenteral solutions.
  • Solutions for parenteral administration preferably contain a water soluble salt of the active ingredient, suitable stabilizing agents, and if necessary, buffer substances.
  • Antioxidizing agents such as sodium bisulfite, sodium sulfite, or ascorbic acid, either alone or combined, are suitable stabilizing agents.
  • citric acid and its salts and sodium EDTA are also used.
  • parenteral solutions can contain preservatives, such as benzalkonium chloride, methyl- or propyl-paraben, and chlorobutanol.
  • Suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, Mack Publishing Company, a standard reference text in this field.
  • Imidazole- 1,2-diamine may also be administered in intranasal form via use of suitable intranasal vehicles, or via transdermal routes, using those forms of transde ⁇ nal skin patches well known to those of ordinary skill in that art. To be administered in the form of a transdermal delivery system, the dosage administration will generally be continuous rather than intermittant throughout the dosage regimen.
  • Parenteral and intravenous forms may also include minerals and other materials to make them compatible with the type of injection or delivery system chosen.
  • Capsules A large number of unit capsules are prepared by filling standard two-piece hard gelatin capsules each with 10 to 500 milligrams of powdered active ingredient, 5 to 150 milligrams of lactose, 5 to 50 milligrams of cellulose, and 6 milligrams magnesium stearate.
  • a mixture of active ingredient in a digestible oil such as soybean oil, cottonseed oil or olive oil is prepared and injected by means of a positive displacement pump into gelatin to form soft gelatin capsules containing 100 - 500 milligrams of the active ingredient.
  • the capsules are washed and dried.
  • a large number of tablets are prepared by conventional procedures so that the dosage unit was 100 - 500 milligrams of active ingredient, 0.2 milligrams of colloidal silicon dioxide, 5 milligrams of magnesium stearate, 50-275 milligrams of microcrystalline cellulose, 11 milligrams of starch and 98.8 milligrams of lactose.
  • Appropriate coatings may be applied to increase palatability or delay absorption.
  • a parenteral composition suitable for administration by injection is prepared by stirring 1.5% by weight of active ingredient in 10% by volume propylene glycol and water. The solution is made isotonic with sodium chloride and sterilized.
  • An aqueous suspension is prepared for oral administration so that each 5 ml contain 100 mg of finely divided active ingredient, 200 mg of sodium carboxymethyl cellulose, 5 mg of sodium benzoate, 1.0 g of sorbitol solution, U.S.P., and 0.025 ml of vanillin.
  • kits useful, for example, for the treatment of cancer which comprise one or more containers containing a pharmaceutical composition comprising a therapeutically effective amount of imidazole-
  • kits may further include, if desired, one or more of various conventional pharmaceutical kit components, such as, for example, containers with one or more pharmaceutically acceptable carriers, additional containers, etc., as will be readily apparent to those skilled in the art.
  • kit components such as, for example, containers with one or more pharmaceutically acceptable carriers, additional containers, etc., as will be readily apparent to those skilled in the art.
  • Printed instructions either as inserts or as labels, indicating quantities of the components to be administered, guidelines for administration, and/or guidelines for mixing the components, may also be included in the kit. It should be understood that although the specified materials and conditions are important in practicing the invention, unspecified materials and conditions are not excluded so long as they do not prevent the benefits of the invention from being realized.
  • the chemotherapeutic agents, imidazole- 1,2-diamine and, optionally, the potentiators are typically mixed with a pharmaceutically acceptable carrier in formulations as described above can be used.
  • the method of treatment can be any suitable method which is effective in the treatment of the particular cancer or tumor type being treated.
  • Treatment may be oral, rectal, topical, parenteral or intravenous administration or by injection into the tumor or cancer.
  • the method of applying an effective amount also varies depending on the disorder or disease being treated. It is believed that parenteral treatment by intravenous, subcutaneous, or intramuscular application of the imidazole- 1,2-diamine, formulated with an appropriate carrier, additional cancer inhibiting compound or compounds or diluent to facilitate application will be the preferred method of administering the compounds to warm blooded animals.
  • Example 2 is used in an in vivo pancreatic (MiaPaCa) cancer nude mouse tumor model, it shows dose responsive efficacy.
  • the data are summarized below.
  • the control is PEG. Both the control and the active are given once a week to the end.
  • the doses were 500 mg/kg, 750 mg/kg and 1000 mg/kg.
  • the surviving animals average tumor weight in mg is:
  • 2-Amino-l-(4-methoxybenzyliden)amino-4-phenylimidazole is prepared by the following synthetic pathway.

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Abstract

This invention is a method of treating cancer, including carcinomas and sarcomas, through the administration of a pharmaceutical composition containing an imidazole-1,2-diamine derivative. The imidazole-1,2-diamine derivative has the formula (I), wherein Y and X are independently selected from the group consisting of hydrogen, halogen, e.g., chloro, fluoro, nitro, methyl, ethyl, oxychloro or alkoxy of less than 7 carbon atoms; n is a positive integer of less than 5; R1 and R2 are independently selected form the group consisting of hydrogen and alkyl of less than 7 carbons; and R is an alkyl of 1 to 6 carbons; and the pharmaceutically acceptable salts and prodrugs thereof.

Description

CANCER TREATMENT
TECHNICAL FIELD A method of treating cancer, including carcinomas and sarcomas is claimed. The pharmaceutical composition containing imidazole-l,2-diamine compounds is also claimed. BACKGROUND OF THE INVENTION
Cancers are a leading cause of death in animals and humans. The exact cause of cancer is not known, but links between certain activities such as smoking or exposure to carcinogens and the incidence of certain types of cancers and tumors has been shown by a number of researchers. Many types of chemotherapeutic agents have been shown to be effective against cancers and tumor cells, but not all types of cancers and tumors respond to these agents. Unfortunately, many of these agents also destroy normal. cells. The exact mechanism for the action of these chemotherapeutic agents is not always known.
Despite advances in the field of cancer treatment the leading therapies to date are surgery, radiation and chemotherapy. Chemotherapeutic approaches are said to fight cancers that are metastasized or ones that are particularly aggressive. Such cytocidal or cytostatic agents work best on cancers with large growth factors, i.e., ones whose cells are rapidly dividing. To date, hormones, in particular estrogen, progesterone and testosterone, and some antibiotics produced by a variety of microbes, alkylating agents, and anti -metabolites form the bulk of therapies available to oncologists. Ideally cytotoxic agents that have specificity for cancer and tumor cells while not affecting normal cells would be extremely desirable. Unfortunately, none have been found and instead agents which target especially rapidly dividing cells (both tumor and normal) have been used.
The development of materials that would target tumor cells due to some unique specificity for them would be a breakthrough. Alternatively, materials that are cytotoxic to tumor cells while exerting mild effects on normal cells are also desirable. SUMMARY OF THE INVENTION A method of treating cancer, in particular, treating cancers in warm blooded animals and humans, comprising administering a therapeutically effective amount of a composition comprising one or more imidazole-l,2-diamine compounds having the formula:
Figure imgf000003_0001
wherein Y and X are independently selected from the group consisting of hydrogen, halogen, e.g., chloro or fluoro, nitro, methyl, ethyl, oxychloro or alkoxy of less than 7 carbon atoms; n is a positive integer of less than 5; Ri and R2 is independently selected from the group consisting of hydrogen and alkyl of less than 7 carbons, and R is an alkyl of from 1 to 6 carbons. Preferably the compound has the formula:
Figure imgf000003_0002
wherein R is methyl, R\or R2 are hydrogen and X and Y are hydrogen and n is 4. The present invention also provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound as described above.
These compositions have been discovered to inhibit the growth of cancer or other tumors in humans or animals by administration of a therapeutically effective amount of the composition, preferably by administering one or more imidazole-l,2-diamine compounds to the site of the cancer. More specifically, this invention provides an anti-cancer composition comprising a pharmaceutical carrier and imidazole-l,2-diamine derivative as defined herein along with a method for treating such cancers.
DETAILED DESCRIPTION OF THE INVENTION A. Definitions:
As used herein, a "pharmaceutically acceptable" component is one that is suitable for use with humans and/or animals without undue adverse side effects (such as toxicity, irritation, and allergic response) commensurate with a reasonable benefit/risk ratio.
As used herein, the term "safe and effective amount" refers to the quantity of a component which is sufficient to yield a desired therapeutic response without undue adverse side effects (such as toxicity, irritation, or allergic response) commensurate with a reasonable benefit/risk ratio when used in the manner of this invention. By
"therapeutically effective amount" is meant an amount of a compound of the present invention effective to yield the desired therapeutic response. For example, an amount effective to delay the growth of or to cause a cancer, either a sarcoma or lymphoma, to shrink or not metastasize. The specific safe and effective amount or therapeutically effective amount will vary with such factors as the particular condition being treated, the physical condition of the patient, the type of mammal being treated, the duration of the treatment, the nature of concurrent therapy (if any), and the specific formulations employed and the structure of the compound or its derivative.
As used herein, a "pharmaceutical salt" is salt of the imidazole-l,2-diamine derivatives which has been modified by making acid or base salts of the compounds. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines. Preferably the salts are made using an organic or inorganic acid. These preferred acid salts are chlorides, bromides, sulfates, nitrates, phosphates, sulfonates, formates, tartrates, maleates, malates, citrates, benzoates, salicylates, ascorbates, and the like.
As used herein, a "pharmaceutical carrier" is a pharmaceutically acceptable solvent, suspending agent or vehicle, for delivering the imidazole-l,2-diamine to the animal or human. The carrier may be liquid or solid and is selected with the planned manner of administration in mind. Liposomes are also a pharmaceutical carrier. As used herein, "cancer" refers to all types of cancer or neoplasm or malignant tumors found in mammals, including carcinomas and sarcomas. Examples of cancers are cancer of the breast, colon, lung, non-small cell lung, melanoma, ovary, prostate and pancreas. The term "leukemia" refers broadly to progressive, malignant diseases of the blood-forming organs and is generally characterized by a distorted proliferation and development of leukocytes and their precursors in the blood and bone marrow. Leukemia is generally clinically classified on the basis of (1) the duration and character of the disease- acute or chronic; (2) the type of cell involved; myeloid (myelogenous), lymphoid (lymphogenous), or monocytic; and (3) the increase or non-increase in the number abnormal cells in the blood- leukemic or aleukemic (subleukemic). The P388 leukemia model is widely accepted as being predictive of in vivo anti-leukemic activity. It is believed that compound that tests positive in the P388 assay will generally exhibit some level of anti-leukemic activity in vivo regardless of the type of leukemia being treated. Accordingly, the present invention includes a method of treating leukemia, and, preferably, a method of treating acute nonlymphocytic leukemia, chronic lymphocytic leukemia, acute granulocytic leukemia, chronic granulocytic leukemia, acute promyelocytic leukemia, adult T-cell leukemia, aleukemic leukemia, a leukocythemic leukemia, basophylic leukemia, blast cell leukemia, bovine leukemia, chronic myelocytic leukemia, leukemia cutis, embryonal leukemia, eosinophilic leukemia, Gross' leukemia, hairy-cell leukemia, hemoblastic leukemia, hemocytoblastic leukemia, histiocytic leukemia, stem cell leukemia, acute monocytic leukemia, leukopenic leukemia, lymphatic leukemia, lymphoblastic leukemia, lymphocytic leukemia, lymphogenous leukemia, lymphoid leukemia, lymphosarcoma cell leukemia, mast cell leukemia, megakaryocytic leukemia, micromyeloblastic leukemia, monocytic leukemia, myeloblastic leukemia, myelocytic leukemia, myeloid granulocytic leukemia, myelomonocytic leukemia, Naegeli leukemia, plasma cell leukemia, plasmacytic leukemia, promyelocytic leukemia, Rieder cell leukemia, Schilling's leukemia, stem cell leukemia, subleukemic leukemia, and undifferentiated cell leukemia. The term "sarcoma" generally refers to a tumor which is made up of a substance like the embryonic connective tissue and is generally composed of closely packed cells embedded in a fibrillar or homogeneous substance. Sarcomas which can be treated with imidazole-l,2-diamine and optionally a potentiator and/or chemotherapeutic agent include a chondrosarcoma, fibrosarcoma, lymphosarcoma, melanosarcoma, myxosarcoma, osteosarcoma, Abernethy's sarcoma, adipose sarcoma, liposarcoma, alveolar soft part sarcoma, ameloblastic sarcoma, botryoid sarcoma, chloroma sarcoma, chorio carcinoma, embryonal sarcoma, Wilms' tumor sarcoma, endometrial sarcoma, stromal sarcoma, Ewing's sarcoma, fascial sarcoma, fibroblastic sarcoma, giant cell sarcoma, granulocytic sarcoma, Hodgkin's sarcoma, idiopathic multiple pigmented hemorrhagic sarcoma, immunoblastic sarcoma of B cells, lymphoma, immunoblastic sarcoma of T-cells, Jensen's sarcoma, Kaposi's sarcoma, Kupffer cell sarcoma, angiosarcoma, leukosarcoma, malignant mesenchymoma sarcoma, parosteal sarcoma, reticulocytic sarcoma, Rous sarcoma, serocystic sarcoma, synovial sarcoma, and telangiectaltic sarcoma.
The term "melanoma" generally refers to a tumor arising from the melanocytic system of the skin and other organs. Melanomas which can be treated with imidazole- 1,2-diamine and optionally a potentiator and/or another chemotherapeutic agent include, for example, acral-lentiginous melanoma, amelanotic melanoma, benign juvenile melanoma, Cloudman's melanoma, S91 melanoma, Harding-Passey melanoma, juvenile melanoma, lentigo maligna melanoma, malignant melanoma, nodular melanoma, subungal melanoma, and superficial spreading melanoma.
The term "carcinoma" refers to a malignant new growth made up of epithelial cells tending to infiltrate the surrounding tissues and give rise to metastases. Exemplary carcinomas which can be treated with imidazole-l,2-diamine and optionally a potentiator and/or a chemotherapeutic agent include, for example, acinar carcinoma, acinous carcinoma, adenocystic carcinoma, adenoid cystic carcinoma, carcinoma adenomatosum, carcinoma of adrenal cortex, alveolar carcinoma, alveolar cell carcinoma, basal cell carcinoma, carcinoma basocellulare, basaloid carcinoma, basosquamous cell carcinoma, bronchioalveolar carcinoma, bronchiolar carcinoma, bronchogenic carcinoma, cerebriform carcinoma, cholangiocellular carcinoma, chorionic carcinoma, colloid carcinoma, comedo carcinoma, corpus carcinoma, cribriform carcinoma, carcinoma en cuirasse, carcinoma cutaneum, cylindrical carcinoma, cylindrical cell carcinoma, duct carcinoma, carcinoma durum, embryonal carcinoma, encephaloid carcinoma, epiermoid carcinoma, carcinoma epitheliale adenoides, exophytic carcinoma, carcinoma ex ulcere, carcinoma fibrosum, gelatiniform carcinoma, gelatinous carcinoma, giant cell carcinoma, carcinoma gigantocellulare, glandular carcinoma, granulosa cell carcinoma, hair-matrix carcinoma, hematoid carcinoma, hepatocellular carcinoma, Hϋrthle cell carcinoma, hyaline carcinoma, hypernephroid carcinoma, infantile embryonal carcinoma, carcinoma in situ, intraepidermal carcinoma, intraepithelial carcinoma, Krompecher's carcinoma, Kulchitzky-cell carcinoma, large-cell carcinoma, lenticular carcinoma, carcinoma lenticulare, lipomatous carcinoma, lymphoepithelial carcinoma, carcinoma medullare, medullary carcinoma, melanotic carcinoma, carcinoma moUe, mucinous carcinoma, carcinoma muciparum, carcinoma mucocellulare, mucoepidermoid carcinoma, carcinoma mucosum, mucous carcinoma, carcinoma myxomatodes, nasopharyngeal carcinoma, oat cell carcinoma, carcinoma ossificans, osteoid carcinoma, papillary carcinoma, periportal carcinoma, preinvasive carcinoma, prickle cell carcinoma, pultaceous carcinoma, renal cell carcinoma of kidney, reserve cell carcinoma, carcinoma sarcomatodes, schneiderian carcinoma, scirrhous carcinoma, carcinoma scroti, signet-ring cell carcinoma, carcinoma simplex, small-cell carcinoma, solanoid carcinoma, spheroidal cell carcinoma, spindle cell carcinoma, carcinoma spongiosum, squamous carcinoma, squamous cell carcinoma, string carcinoma, carcinoma telangiectaticum, carcinoma telangiectodes, transitional cell carcinoma, carcinoma tuberosum, tuberous carcinoma, verrucous carcinoma, and carcinoma villosum.
Additional cancers which can be treated with imidazole-l,2-diamine according to the invention include, for example, Hodgkin's Disease, Non-Hodgkin's Lymphoma, multiple myeloma, neuroblastoma, breast cancer, ovarian cancer, lung cancer, rhabdomyosarcoma, primary thrombocytosis, primary macroglobulinemia, small-cell lung tumors, primary brain tumors, stomach cancer, colon cancer, malignant pancreatic insulanoma, malignant carcinoid, urinary bladder cancer, premalignant skin lesions, testicular cancer, lymphomas, thyroid cancer, esophageal cancer, genitourinary tract cancer, malignant hypercalcemia, cervical cancer, endometrial cancer, adrenal cortical cancer, and prostate cancer. As used herein, the "imidazole-l,2-diamine" or "imidazole-l,2-diamine derivatives" or "imidazole-l,2-diamine compounds" are the compounds of the formula:
Figure imgf000008_0001
wherein Y and X are independently selected from the group consisting of hydrogen, halogen, e.g., chloro, fluoro, nitro, methyl, ethyl, oxychloro or alkoxy of less than 7 carbon atoms; n is a positive integer of less than 5; Ri and R2 are independently selected from the group consisting of hydrogen and alkyl of less than 7 carbons; and R is an alkyl of from 1 to 6 carbons; and its pharmaceutically safe salts and prodrugs thereof. More specific imidazole-l,2-diamines are described in detail below.
By "alkyl" as used herein is meant a straight, branched or cyclic alkane derivatives.
As used herein "combination therapy" or "adjunct therapy" means that the patient in need of the drug is treated or given another drug for the disease in conjunction with the imidazole-l,2-diamine derivatives. This combination therapy can be sequential therapy where the patient is treated first with one drug and then the other or the two drugs are given simultaneously.
B. THE IMIDAZOLE-1.2-DIAMINE DERIVATIVES The imidazole-1, 2-diamine compounds have the following structure:
Figure imgf000009_0001
wherein Y and X are independently selected form the group consisting of hydrogen, halogen, e.g., chloro, fluoro, nitro, methyl, ethyl, oxychloro or alkoxy of less than 7 carbon atoms; n is a positive integer of less than 5;
Figure imgf000009_0002
and R2 are independently selected from the group consisting of hydrogen and alkyl of less than 7 carbons; and R is alkyl of 1 to 6 carbons. Preferably the compositions are:
Figure imgf000009_0003
wherein R is methyl, Rj and R2 are hydrogen and X and Y are hydrogen and n is 4; and the non-toxic, pharmaceutically acceptable acid salts with both organic and inorganic acids.
The imidazole-l,2-diamine compounds also include prodrugs. "Prodrugs" are considered to be any covalently bonded carriers which release the active parent drug according to the formula of the imidazole-l,2-diamine derivatives described above in vivo when such prodrug is administered to a mammalian subject. Prodrugs of the imidazole-l,2-diamine compounds are prepared by modifying functional groups present in the compounds in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compounds. Prodrugs include compounds wherein hydroxy, amine, or sulfhydryl groups are bonded to any group that, when administered to a mammalian subject, cleaves to form a free hydroxyl, amino, or sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate, or benzoate derivatives of alcohol and amine functional groups in the imidazole-1,2- diamine; phosphate esters, dimethylglycine esters, aminoalkylbenzyl esters, aminoalkyl esters and carboxyalkyl esters of alcohol or phenol functional groups in the imidazole- 1,2-diamine; and the like.
The pharmaceutically acceptable salts of the imidazole-l,2-diamine include the conventional non-toxic salts or the quaternary ammonium salts of the imidazole-1,2- diamine formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, formic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like. A pharmaceutically acceptable salt of the present invention is synthesized from the imidazole-l,2-diamine derivatives which contain a basic moiety by conventional chemical methods. Generally, such salts are prepared by reacting the free base forms of these compounds with a stoichiometric amount of the appropriate acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418. SYNTHESIS
The imidazole-l,2-diaminederivatives are prepared in a number of ways well known to one skilled in the art of organic synthesis.
The compounds are made by standard methods known in the literature. For example, 2-amino-l-(4-methoxybenzyliden)amino-4-phenylimidazole is prepared by reacting N-amidino-N' - (4-methoxybenizylidene)hydrazone and 2-bromoacetophenone (see, M.Z. Krimer, et al., Chemistry ofHeterocyclic Compounds, 9, 1209-1213 (Russian) 1999; (English, pp. 1035-1039). The N-amidino-N' - (4-methoxybenizylidene)hydrazone is made by reacting p-anisaldehyde and aminoguanidinium nitrate in the presence of potassium hydroxide in ethanol (A. F. Hegarty, et al, J Chem. Soc, Perkin II, 1973, 2047-2054). The synthesis is described in Example 2.
One skilled in the art of organic synthesis can modify these reaction to make the other compounds used herein. COMBINATION THERAPY
In some embodiments, imidazole-l,2-diamine is used in combination with one or more potentiators and/or chemotherapeutic agents for the treatment of cancer or tumors. An exemplary potentiator is triprolidine or its cis-isomer which are used in combination with chemotherapeutic agents and imidazole-l,2-diamine. Triprolidine is described in US 5,114,951 (1992). Another potentiator is procodazole, lH-Benzimidazole-2- propanoic acid; [β-(2-benzimidazole) propionic acid; 2-(2-carboxyethyl)benzimidazole; propazol]. Procodazole is a non-specific immunoprotective agent active against viral and bacterial. It is effective with imidazole-l,2-diamine in treating cancers, tumors or leukemia. Procodazole can also be combined with imidazole-l,2-diamine and other chemotherapeutic agents to treat cancer, tumor or leukemia.
Other potentiators which can be used with imidazole-l,2-diamine and optionally another chemotherapeutic agent to treat or inhibit the growth of cancer include monensin, an anti-sense inhibitor of the RAD51 gene, bromodeoxyuridine, dipyridamole, indomethacin, a monoclonal antibody, an anti-transferrin receptor immunotoxin, metoclopramide, 7-thia-8-oxoguanosine, N-solanesyl-N,N'-bis(3,4- dimethoxybenzyl)ethylenediamine, leucovorin, heparin, N-[4-[(4- fluorphenyl)sulfonly]phenyl] acetamide, heparin sulfate, cimetidine, a radiosensitizer, a chemosensitizer, a hypoxic cell cytotoxic agent, muramyl dipeptide, vitamin A, 2'-deoxycoformycin, a bis-diketopiperazine derivative, and dimethyl sulfoxide. The chemotherapeutic agents which can be used with imidazole-l,2-diamine and an optional potentiator are generally grouped as DNA-interactive Agents, Antimetabolites, Tubulin-Interactive Agents, Hormonal agents and others such as Asparaginase or hydroxyurea. Each of the groups of chemotherapeutic agents can be further divided by type of activity or compound. The chemotherapeutic agents used in combination with imidazole-l,2-diamine include members of all of these groups. For a detailed discussion of chemotherapeutic agents and their method of administration, see Dorr, et al, Cancer Chemotherapy Handbook, 2d edition, pages 15-34, Appleton & Lange (Connecticut, 1994).
DNA-Interactive Agents include the alkylating agents, e.g. Cisplatin,
Cyclophosphamide, Altretamine; the DNA strand-breakage agents, such as Bleomycin; the intercalating topoisomerase II inhibitors, e.g., Dactinomycin and Doxorubicin); the nonintercalating topoisomerase II inhibitors such as, Etoposide and Teniposde; and the
DNA minor groove binder Plicamydin.
The alkylating agents form covalent chemical adducts with cellular DNA, RNA, and protein molecules and with smaller amino acids, glutathione and similar chemicals. Generally, these alkylating agents react with a nucleophilic atom in a cellular constituent, such as an amino, carboxyl, phosphate, sulfhydryl group in nucleic acids, proteins, amino acids, or glutathione. The mechanism and the role of these alkylating agents in cancer therapy is not well understood. Typical alkylating agents include:
Nitrogen mustards, such as Chlorambucil, Cyclophosphamide, Isofamide, Mechlorethamine, Melphalan, Uracil mustard; Aziridine such as Thiotepa; methanesulphonate esters such as Busulfan; nitroso ureas, such as Carmustine, Lomustine, Streptozocin; platinum complexes, such as Cisplatin, Carboplatin; bioreductive alkylator, such as Mitomycin, and Procarbazine, Dacarbazine and
Altretamine.
DNA strand breaking agents include Bleomycin. DNA topoisomerase II inhibitors include the following:
Intercalators, such as Amsacrine, Dactinomycin, Daunorubicin, Doxorubicin, Idarubicin, and Mitoxantrone; and nonintercalators, such as Etoposide and Teniposide. The DNA minor groove binder is Plicamycin.
The antimetabolites interfere with the production of nucleic acids by one or the other of two major mechanisms. Some of the drugs inhibit production of the deoxyribonucleoside triphosphates that are the immediate precursors for DNA synthesis, thus inhibiting DNA replication. Some of the compounds are sufficiently like purines or pyrimidines to be able to substitute for them in the anabolic nucleotide pathways. These analogs can then be substituted into the DNA and RNA instead of their normal counterparts. The antimetabolites useful herein include: folate antagonists such as Methotrexate and trimetrexate pyrimidine antagonists, such as Fluorouracil, Fluorodeoxyuridine, CB3717,
Azacitidine and Floxuridine purine antagonists such as Mercaptopurine, 6-Thioguanine, Pentostatin; sugar modified analogs such as Cytarabine and Fludarabine; and ribonucleotide reductase inhibitors such as hydroxyurea. Tubulin Interactive agents act by binding to specific sites on tubulin, a protein that polymerizes to form cellular microtubules. Microtubules are critical cell structure units. When the interactive agents bind on the protein, the cell can not form microtubules Tubulin Interactive agents include colchicine, Vincristine and Vinblastine, both alkaloids and Paclitaxel and cytoxan. Hormonal agents are also useful in the treatment of cancers and tumors. They are used in hormonally susceptible tumors and are usually derived from natural sources. These include: estrogens, conjugated estrogens and Ethinyl Estradiol and Diethylstilbesterol, Chlortrianisen and Idenestrol; progestins such as Hydroxyprogesterone caproate, Medroxyprogesterone, and
Megestrol; and androgens such as testosterone, testosterone propionate; fluoxymesterone, methyltestosterone.
Adrenal corticosteroids are derived from natural adrenal cortisol or hydrocortisone. They are used because of their anti inflammatory benefits as well as the ability of some to inhibit mitotic divisions and to halt DNA synthesis. These compounds include, Prednisone, Dexamethasone, Meth lprednisolone, and Prednisolone.
Leutinizing hormone releasing hormone agents or gonadotropin-releasing hormone antagonists are used primarily the treatment of prostate cancer. These include leuprolide acetate and goserelin acetate. They prevent the biosynthesis of steroids in the testes. Antihormonal antigens include: antiestrogenic agents such as Tamoxifen, antiandrogen agents such as Flutamide; and antiadrenal agents such as Mitotane and Aminoglutethimide. Hydroxyurea, which appears to act primarily through inhibition of the enzyme ribonucleotide reductase, can also be used in combination with imidazole-l,2-diamine.
Asparaginase is an enzyme which converts asparagine to nonfunctional aspartic acid and thus blocks protein synthesis in the tumor. Asparaginase can also be used in combination with imidazole-l,2-diamine to treat cancer. DOSAGE
Imidazole-l,2-diamine is preferably micronized or powdered so that it is more easily dispersed and solubilized by the body. Processes for grinding or pulverizing drugs are well known in the art. For example, a hammer mill or similar milling device are used. The preferred particle size is less than about lOOμ and preferably less than 50μ. Dosage forms (compositions) suitable for internal administration contain from about 1.0 milligram to about 5000 milligrams of active ingredient per unit. In these pharmaceutical compositions, the active ingredient will ordinarily be present in an amount of about 0.5-95% by weight based on the total weight of the composition. Based on the body weight of the patient, the dosage may be administered in one or more doses several times per day or per week. Multiple dosage units may be required to achieve a therapeutically effective amount. For example, if the dosage form is 1000 mg, and the patient weighs 40 kg, one pill will provide a dose of 25 mg per kg for that patient. It will provide a dose of only 12.5 mg/kg for a 80 kg patient.
Imidazole-l,2-diamine has exhibited efficacy in vivo against cancers in mice at doses of about 500 mg/kg, 750 mg/kg and 1000 mg/kg. Generally, an effective dose in mice is about 12 times the expected effective dose in humans. By way of general guidance, for humans a dosage of as little as about 25 milligrams (mg) per kilogram (kg) of body weight and up to about 10000 mg per kg of body weight is suitable as a therapeutically effective dose. Preferably, from about 40 mg/kg to about 2500 mg/kg of body weight is used. Other preferred doses range between 100 mg/kg to about 3000 mg/kg of body weight. However, a dosage of between about 2 milligrams (mg) per kilogram (kg) of body weight to about 400 mg per kg of body weight is also suitable for treating some cancers.
Intravenously, the most preferred rates of administration may range from about 1 to about 1000 mg/kg/minute during a constant rate infusion. Imidazole-l,2-diamine may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three, or four times daily. Imidazole-l,2-diamine is generally given in one or more doses on a daily basis or from one to three times a week.
Imidazole-l,2-diamine is administered by any conventional means available for use in conjunction with pharmaceuticals, either as individual therapeutic agents or in combination with other therapeutic agents
The amount and identity of a chemotherapeutic agent that is used with imidazole- 1,2-diamine in treating cancer, tumor, leukemia, or other related diseases will vary according to patient response and physiology, type and severity of side effects, disease being treated, dosing regimen, patient prognosis or other such factors. When imidazole-l,2-diamine is used in combination with other therapeutic agents, the ratio of imidazole-l,2-diamine to the other therapeutic agent will be varied as needed according to the desired therapeutic effect, the observed side-effects of the combination, or other such considerations known to those of ordinary skill in the medical arts. Generally, the ratio of imidazole-l,2-diamine to other therapeutic agent will range from about 0.5% : 99.5% to about 99.5% : 0.5% on a weight basis.
When imidazole-l,2-diamine is administered before or after other therapeutic agents to treat cancer, tumors, or other diseases, the respective doses and the dosing regimen of imidazole-l,2-diamine and the other therapeutic agent may vary. The adjunct or combination therapy can be sequential, that is the treatment with one agent first and then the second agent, or it can be concomitant treatment wherein two or more agents are administered substantially at the same time. The sequential therapy can be within a reasonable time after the completion of the first therapy before beginning the second therapy. The treatment with both agents at the same time can be in the same daily dose or in separate doses. For example treatment with one agent on day 1 and the other on day 2. The exact regimen will depend on the disease being treated, the severity of the disease and the response to the treatment. For example, a full dosing regimen of imidazole- 1,2-diamine can be administered either before or after a full dosing regimen of the other therapeutic agent, or alternating doses of imidazole- 1,2-diamine and the other therapeutic agent may be administered. As a further example, imidazole- 1,2-diamine can be administered concomitantly with the other therapeutic agent.
The identity of the chemotherapeutic agent, the pharmaceutical carrier and the amount of compound administered will vary widely depending on the species and body weight of mammal and the type of cancer being treated. The dosage administered will vary depending upon known factors, such as the pharmacodynamic characteristics of a specific chemotherapeutic agent and its mode and route of administration; the age, sex, metabolic rate, absorptive efficiency, health and weight of the recipient; the nature and extent of the symptoms; the kind of concurrent treatment being administered; the frequency of treatment; and the desired therapeutic effect.
Imidazole- 1,2-diamine, the potentiator and/or the chemotherapeutic agent are administered together in a single dosage form or separately in two or more different dosage forms. These can be administered independently by the same route or by two or more different routes of administration depending on the dosage forms employed.
Suitable pharmaceutical compositions and dosage forms will preferably comprise imidazole- 1,2-diamine, a potentiator and optionally a chemotherapeutic agent. The ratio of imidazole- 1,2-diamine to potentiator is generally in the range of about 1:0.01 to 10:1, and preferably 1:0.05 to 1:1 on a weight basis.
One skilled in the art will be able to ascertain the appropriate dose. DOSAGE FORM
A dosage unit may comprise a single compound or mixtures thereof with other anti-cancer compounds, other cancer or tumor growth inhibiting compounds. Imidazole- 1,2-diamine can be administered in oral dosage forms as tablets, capsules, pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions. Imidazole- 1,2-diamine may also be administered in intravenous (bolus or infusion), intraperitoneal, subcutaneous, or intramuscular form, all using dosage forms well known to those of ordinary skill in the pharmaceutical arts. Imidazole- 1,2-diamine is typically administered in admixture with suitable pharmaceutical diluents, extenders, excipients, or carriers (collectively referred to herein as a pharmaceutically acceptable carrier or carrier materials) suitably selected with respect to the intended form of administration and as consistent with conventional pharmaceutical practices. The unit will be in a form suitable for oral, rectal, topical, intravenous injection or parenteral administration.
Imidazole- 1,2-diamine can be administered alone but is generally mixed with a pharmaceutically acceptable carrier. This carrier can be a solid or liquid, and the type of carrier is generally chosen based on the type of administration being used. Specific examples of pharmaceutical acceptable carriers and excipients that may be used to formulate oral dosage forms of the present invention are described in U. S. Pat. No. 3,903,297 to Robert, issued Sept. 2, 1975. Techniques and compositions for making dosage forms useful in the present invention are described in the following references: 7 Modern Pharmaceutics, Chapters 9 and 10 (Banker & Rhodes, Editors, 1979); Pharmaceutical Dosage Forms: Tablets (Lieberman et al., 1981); Ansel, Introduction to Pharmaceutical Dosage Forms 2nd Edition (1976); Remington's Pharmaceutical Sciences, 17th ed. (Mack Publishing Company, Easton, Pa., 1985); Advances in Pharmaceutical Sciences (David Ganderton, Trevor Jones, Eds., 1992); Advances in Pharmaceutical Sciences Vol 7. (David Ganderton, Trevor Jones, James McGinity, Eds., 1995); Aqueous Polymeric Coatings for Pharmaceutical Dosage Forms (Drugs and the Pharmaceutical Sciences, Series 36 (James McGinity, Ed., 1989); Pharmaceutical Particulate Carriers : Therapeutic Applications: Drugs and the Pharmaceutical Sciences, Vol 61 (Alain Rolland, Ed., 1993); Drug Delivery to the Gastrointestinal Tract (Ellis Horwood Books in the Biological Sciences. Series in Pharmaceutical Technology; J. G. Hardy, S. S. Davis, Clive G. Wilson, Eds.); Modern Pharmaceutics Drugs and the Pharmaceutical Sciences, Vol 40 (Gilbert S. Banker, Christopher T. Rhodes, Eds.).
Tablets may contain suitable binders, lubricants, disintegrating agents, coloring agents, flavoring agents, flow-inducing agents, and melting agents. For instance, for oral administration in the dosage unit form of a tablet or capsule, the active drug component can be combined with an oral, non-toxic, pharmaceutically acceptable, inert carrier such as lactose, gelatin, agar, starch, sucrose, glucose, methyl cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like.
Suitable binders include starch, gelatin, natural sugars such as glucose or beta- lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth, or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and the like. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like. Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum, and the like. Imidazole- 1,2-diamine can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamallar vesicles, and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine, or phosphatidylcholines.
Imidazole- 1,2-diamine may also be coupled to soluble polymers as targetable drug carriers or as a prodrug. Such polymers include polyvinylpyrrolidone, pyran copolymer, polyhydroxylpropylmethacrylamide-phenol, polyhydroxyethylasparta-midephenol, or polyethyleneoxide-polylysine substituted with palmitoyl residues. Furthermore, imidazole- 1,2-diamine may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacylates, and crosslinked or amphipathic block copolymers of hydrogels.
Gelatin capsules may contain the active ingredient and powdered carriers, such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like. Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as immediate release products or as sustained release products to provide for continuous release of medication over a period of hours. Compressed tablets can be sugar coated or film coated to mask any unpleasant taste and protect the tablet from the atmosphere, or enteric coated for selective disintegration in the gastrointestinal tract. For oral administration in liquid dosage form, the oral drug components are combined with any oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like. Examples of suitable liquid dosage forms include solutions or suspensions in water, pharmaceutically acceptable fats and oils, alcohols or other organic solvents, including esters, emulsions, syrups or elixirs, suspensions, solutions and/or suspensions reconstituted from non-effervescent granules and effervescent preparations reconstituted from effervescent granules. Such liquid dosage forms may contain, for example, suitable solvents, preservatives, emulsifying agents, suspending agents, diluents, sweeteners, thickeners, and melting agents.
Liquid dosage forms for oral administration can contain coloring and flavoring to increase patient acceptance. In general, water, a suitable oil, saline, aqueous dextrose (glucose), and related sugar solutions and glycols such as propylene glycol or polyethylene glycols are suitable carriers for parenteral solutions. Solutions for parenteral administration preferably contain a water soluble salt of the active ingredient, suitable stabilizing agents, and if necessary, buffer substances. Antioxidizing agents such as sodium bisulfite, sodium sulfite, or ascorbic acid, either alone or combined, are suitable stabilizing agents. Also used are citric acid and its salts and sodium EDTA. In addition, parenteral solutions can contain preservatives, such as benzalkonium chloride, methyl- or propyl-paraben, and chlorobutanol. Suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, Mack Publishing Company, a standard reference text in this field. Imidazole- 1,2-diamine may also be administered in intranasal form via use of suitable intranasal vehicles, or via transdermal routes, using those forms of transdeπnal skin patches well known to those of ordinary skill in that art. To be administered in the form of a transdermal delivery system, the dosage administration will generally be continuous rather than intermittant throughout the dosage regimen. Parenteral and intravenous forms may also include minerals and other materials to make them compatible with the type of injection or delivery system chosen.
Useful pharmaceutical dosage forms for administration of imidazole- 1,2-diamine are illustrated as follows: Capsules A large number of unit capsules are prepared by filling standard two-piece hard gelatin capsules each with 10 to 500 milligrams of powdered active ingredient, 5 to 150 milligrams of lactose, 5 to 50 milligrams of cellulose, and 6 milligrams magnesium stearate.
Soft Gelatin Capsules
A mixture of active ingredient in a digestible oil such as soybean oil, cottonseed oil or olive oil is prepared and injected by means of a positive displacement pump into gelatin to form soft gelatin capsules containing 100 - 500 milligrams of the active ingredient. The capsules are washed and dried.
Tablets
A large number of tablets are prepared by conventional procedures so that the dosage unit was 100 - 500 milligrams of active ingredient, 0.2 milligrams of colloidal silicon dioxide, 5 milligrams of magnesium stearate, 50-275 milligrams of microcrystalline cellulose, 11 milligrams of starch and 98.8 milligrams of lactose.
Appropriate coatings may be applied to increase palatability or delay absorption.
Injectable solution A parenteral composition suitable for administration by injection is prepared by stirring 1.5% by weight of active ingredient in 10% by volume propylene glycol and water. The solution is made isotonic with sodium chloride and sterilized.
Suspension
An aqueous suspension is prepared for oral administration so that each 5 ml contain 100 mg of finely divided active ingredient, 200 mg of sodium carboxymethyl cellulose, 5 mg of sodium benzoate, 1.0 g of sorbitol solution, U.S.P., and 0.025 ml of vanillin.
Kits
The present invention also includes pharmaceutical kits useful, for example, for the treatment of cancer, which comprise one or more containers containing a pharmaceutical composition comprising a therapeutically effective amount of imidazole-
1,2-diamine. Such kits may further include, if desired, one or more of various conventional pharmaceutical kit components, such as, for example, containers with one or more pharmaceutically acceptable carriers, additional containers, etc., as will be readily apparent to those skilled in the art. Printed instructions, either as inserts or as labels, indicating quantities of the components to be administered, guidelines for administration, and/or guidelines for mixing the components, may also be included in the kit. It should be understood that although the specified materials and conditions are important in practicing the invention, unspecified materials and conditions are not excluded so long as they do not prevent the benefits of the invention from being realized. The chemotherapeutic agents, imidazole- 1,2-diamine and, optionally, the potentiators are typically mixed with a pharmaceutically acceptable carrier in formulations as described above can be used.
D. METHOD OF TREATMENT
The method of treatment can be any suitable method which is effective in the treatment of the particular cancer or tumor type being treated. Treatment may be oral, rectal, topical, parenteral or intravenous administration or by injection into the tumor or cancer. The method of applying an effective amount also varies depending on the disorder or disease being treated. It is believed that parenteral treatment by intravenous, subcutaneous, or intramuscular application of the imidazole- 1,2-diamine, formulated with an appropriate carrier, additional cancer inhibiting compound or compounds or diluent to facilitate application will be the preferred method of administering the compounds to warm blooded animals.
One skilled in the art will recognize that the efficacy of the imidazole- 1,2-diamine compounds can be ascertained through routine screening using known cancer cell lines both in vitro and in vivo. Cell lines are available from American Tissue Type Culture or other laboratories.
The following examples are illustrative and not intended to be limiting of the invention.
Example 1 When 2-amino-l-(4-methoxybenzyliden)amino-4-phenylimidazole as prepared in
Example 2 is used in an in vivo pancreatic (MiaPaCa) cancer nude mouse tumor model, it shows dose responsive efficacy. The data are summarized below. The control is PEG. Both the control and the active are given once a week to the end. The doses were 500 mg/kg, 750 mg/kg and 1000 mg/kg. The surviving animals average tumor weight in mg is:
Figure imgf000022_0001
Similar dose responsive results are achieved when the compound is used in a study using the HT29 Colon model. Example 2
2-Amino-l-(4-methoxybenzyliden)amino-4-phenylimidazole is prepared by the following synthetic pathway.
Figure imgf000023_0001
KOH/EtOH
Figure imgf000023_0002
Synthesis of 2-amino- 1 -(4methoxybenzyliden amino-4-phenylimidazole
N- Amidino-N'-(4-methoxybenzylidene')hvdrazone:
Equimolar quantities of p-anisaldehyde (50 g, 0.367 mol) and aminiguanidinium nitrate (50.4g, 0.367 mol) in ethanol/water (500 ml/200ml) containing potassium hydroxide (36g, 0.55 mol) were refluxed for 30 min. The mixture was cooled in an ice- bath and the resulting white precipitate was filtered, washed with water and dried (Na2SO4)
2-amino- 1 -(4-methoxybenzyliden)amino-4-phenylimidazole: A solution of potassium hydroxide (17.3 g. 0.31 mol) in ethanol (232 mL) was added drop wise over 6 h to a stirred solution of 2-bromoacetophenone (61.4 g, 0.31 mol) in 464 mL of ethanol. The reaction mixture warmed to ca 33 °C and a precipitated formed. The mixture was stirred at room temperature overnight and the resulting precipitate was filtered and washed with hot water, dried, and crystallized from 1,4-dioxane. Product was washed with ethanol/ether (1 :2) and dried to give 34.7g of product.

Claims

WHAT IS CLAIMED IS:
1. Use of a pharmaceutical composition comprising an imidazole- 1 ,2-diamine compound having the formula:
Figure imgf000025_0001
wherein
Y and X are independently selected from the group consisting of hydrogen, halogen, nitro, methyl, ethyl, oxychloro, or alkoxy of less than 7 carbon atoms; n is a positive integer of less than 5;
Ri and R2 are independently selected from the group consisting of hydrogen and alkyl of less than 7 carbons; and
R is alkyl of from 1 to 6 carbons or the pharmaceutical acceptable salt or prodrug thereof for treating cancer in a patient in need thereof.
2. A use according to Claim 1 wherein said cancer is selected from the group consisting of prostate cancer, melanoma, leukemia, pancreatic cancer, neuroblastoma, cervical cancer, ovarian cancer, stomach cancer, a sarcoma, a lymphoma, breast cancer, lung cancer, colon cancer.
3. A use according to Claim 1 or 2 wherein said imidazole- 1,2-diamine compound has the following formula:
Figure imgf000026_0001
4. A pharmaceutical composition comprising a therapeutically effective amount of a composition comprising a imidazole- 1,2-diamine compound having the formula:
Figure imgf000026_0002
wherein
Y and X are independently selected from the group consisting of hydrogen, halogen, nitro, methyl, ethyl, oxychloro, or alkoxy of less than 7 carbon atoms; n is a positive integer of less than 5;
R! and R2 are independently selected from the group consisting of hydrogen and alkyl of less than 7 carbons; and
R is alkyl of from 1 to 6 carbons.
5. A pharmaceutical composition according to claim 4 further comprising a pharmaceutical carrier.
6. A pharmaceutical composition according to claims 4 or 5 further comprising a safe and effective amount of a potentiator.
7. A pharmaceutical composition according to Claims 4, 5 or 6, wherein said potentiator is selected from the group consisting of procodazole, triprolidine, propionic acid, monensin, an anti-sense inhibitor of the RAD51 gene, bromodeoxyuridine, dipyridamole, indomethacin, a monoclonal antibody, an anti-transferrin receptor immunotoxin, metoclopramide, 7-thia-8-oxoguanosine, N-solanesyl-N,N'-bis(3,4- dimethoxybenzyl)ethylenediamine, N-[4-[(4-fluorphenyl)sulfonly]phenyl] acetamide, leucovorin, heparin, heparin sulfate, cimetidine, a radiosensitizer, a chemosensitizer, a hypoxic cell cytotoxic agent, muramyl dipeptide, vitamin A, 2'-deoxycoformycin, a bis- diketopiperazine derivative, and dimethyl sulfoxide. further comprising a potentiator.
8. A pharmaceutical composition according to claims 4,5,6 or 7 further comprising a safe and effective amount of a chemotherapeutic agent.
9. A pharmaceutical composition according to claim 8 wherein said chemotherapeutic agent is selected from the group consisting of a DNA-interactive agent, an alkylating agent, an antimetabolite, a tubulin-interactive agent, and a hormonal agent.
10. Use of a combination therapy to treat a cancer a patient in need thereof wherein said combination therapy comprises:
i) a therapeutically effective amount of an imidazole- 1,2-diamine compound having the formula:
Figure imgf000027_0001
wherein
Y and X are independently selected from the group consisting of hydrogen, halogen, nitro, methyl, ethyl, oxychloro, or alkoxy of less than 7 carbon atoms; n is a positive integer of less than 5; Ri and R2 are independently selected from the group consisting of hydrogen and alkyl of less than 7 carbon atoms; and R is alkyl of from 1 to 6 carbon atoms; and ii) a safe and effective amount of a chemotherapeutic agent.
11. A use according to Claim 12 wherein said cancer treated is selected from the group consisting of prostate cancer, melanoma, leukemia, pancreatic cancer, neuroblastoma, cervical cancer, ovarian cancer, stomach cancer, a sarcoma, a lymphoma, breast cancer, lung cancer, colon cancer.
12. A use according to Claim 11 wherein said imidazole- 1 ,2-diamine compound has the following formula:
Figure imgf000028_0001
13. A use according to claims 11 or 12 wherein said chemotherapeutic agent is selected from the group consisting of a DNA-interactive Agents, an alkylating agent, an antimetabolite, a tubulin-interactive agents, and a hormonal agent.
14. A use according to claims 11, 12 , or 13 wherein said combination therapy further comprising a safe and effective amount of a potentiator.
15. A composition according to claim 4 wherein said composition is the form of a liposome.
16. A liposome composition according to claim 15 wherein said liposome is unilamellar vesicles or multilamellar vesicles.
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WO2008094319A3 (en) * 2007-02-01 2009-02-19 Univ Texas Methods and compositions of trail-death receptor agonists/activators
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